This invention relates to the treatment of patients suffering from or at risk of septic shock caused by bacteremic infections. More particularly, this invention relates to the prophylaxis of incipient septic shock and to the amelioration of the symptoms characteristic of acute septic shock.
Septic shock is a widespread and hazardous syndrome that frequently accompanies severe Gram-negative and, to a lesser degree, Gram-positive bacteremia. According to recent studies, in a hypothetical group of 100 patients who are bacteremic with Gram-negative organisms, the incidence of metabolic complications and shock is about 25%, while about 10% of patients with Gram-positive bacteremia (especially from S. aureus infections) develop shock.
The presence of bacteremic shock dramatically increases morbidity and mortality. In cases in which the inciting infection is localized, shock is associated with a 50% mortality. Frank shock accompanying systemic bacteremia is characterized by greater than 70% mortality. In addition, recovery from the effects of shock and bacteremia typically requires long-term intensive care at great expense.
Gram-negative rods such as Enterobacteriaceae and Pseudomonadeaceae are normal habitants of the digestive tract that invade the bloodstream of patients who receive immunosuppressive therapy or suffer from serious underlying trauma or disease, such as severe thermal burns or other serious injuries, cystic fibrosis, renal insufficiency, malignant neoplastic diseases, major surgical procedures, or organ transplantations.
The classic septic shock syndrome results primarily from the sequence of events triggered by bacteremia during which cell wall bacterial substances (endotoxin in Gram-negative organisms and the peptidoglycan/teichoic acid complex in Gram-positive organisms) activate the complement, coagulation, kinin and ACTH/endorphin systems. This activation results in a series of metabolic events that ultimately progress to a state of shock.
Incipient septic shock is characterized by the following: Body temperature extremes (fever &gt;40.6.degree. C. or hypothermia), altered mental status, orthostatic blood pressure decrease (&gt;30 mm Hg), decreasing urine output, unexplained edema usually associated with a falling serum albumin concentration, tachypnea with hypoxemia, and/or the development of a metabolic acidosis, elevated serum lactate, leukopenia (predominantly neutropenia), and thrombocytopenia with or without petechial skin rash.
Septic shock related to bacteremic infections advances in two hemodynamic stages. First, patients demonstrate symptoms characteristic of vasomotor effect following ACTH/endorphin release, kallikrein-kinin system activation, and histamine release induced by bacterial cell wall components or toxins. As these symptoms develop, complement-mediated leukoagglutination and capillary damage (primary due to the intracapillary adherence and aggregation of activated polymorphonuclear leukocytes) cause a severe capillary leak syndrome followed by a dramatic fall in intravascular blood volume, decline in cardiac output, and disseminated intravascular coagulation.
Obviously, early diagnosis and therapy of patients at risk from septic shock is desirable. At the present time, prophylactic measures include strict adherence to infection control measures, antibiotic and intravenous fluid therapy, immunoprophylaxis, and granulocyte transfusions.
Anti-shock therapy commonly includes volume replacement using plasma expanders such as 5% albumin, isotonic saline, or lactated Ringer's solution under continuous hemodynamic monitoring. Just enough fluid is supplied to bring the patient's pulmonary capillary wedge pressure to the high normal range. Vasoactive compounds such as dopamine dobutamine, norepinephrine, etc. are used when volume replacement is not sufficient. In addition, anti-inflammatory drugs such as methylprednisolone sodium succinate may be used in large doses (up to 30 mg/kg). Anti-prostaglandins have been proposed for the suppression of inflammatory damage caused by the activated peripheral polymorphonuclear leukocytes.
Finally, mortality from bacteremic infections has been reduced by using substances such as mafenide acetate or silver salts that inhibit bacterial colonization of the burn wound surface and by using potent anti-microbial agents, sympathomimetic amines, corticosteroids, anti-coagulants, granulocyte transfusion, and diuretics for treating bacteremia as primary or adjunct therapy.
Such measures, however, have only proved partially successful in controlling the morbidity and mortality associated with endotoxin or septic shock. Antibiotic therapy may possibly exacerbate incipient toxic shock by inducing the release of bacteria cell wall material and toxins. Vasopressors do not ameliorate capillary damage, anti-inflammatory therapies are controversial, and volume replacement is at best a stop-gap therapy resulting in edema and cardiac complications.
The transforming growth factor-.beta. molecules identified thus far are two-chain molecules containing two identical 112 residue polypeptide chains linked by disulfide bonds. The molecular mass of these dimers is about 25 kd. Biologically active TGF-.beta. has been defined as a molecule capable of inducing anchorage independent growth of target cell lines or rat fibroblasts in in vitro cell culture, when added together with EGF or TGF-.alpha. as a co-factor. Suitable methods are known for purifying TGF-.beta. from platelets or placenta, for producing it in recombinant cell culture and for determining its activity. See, for example, R. Derynck et al., Nature, 316:701 (1985) and U.S.S.N.s 715,142; 500,832; 500,833, all abandoned; European Pat. Pub. Nos. 200,341 published Dec. 10, 1986, published Jan. 22, 1986, 268,561 published May 25, 1988, and 267,463 published May 18, 1988; GB Pat. Appln. 2,146 335 published Apr. 17, 1985; U.S. Pat. No. 4,774,322; Seyedin et al, J. Biol. Chem., 262: 1946-1949 (1987); and Cheifetz et al, Cell 48: 409-415 (1987), the entire contents thereof being expressly incorporated by reference.
TGF-.beta. has been shown to have numerous regulatory actions on a wide variety of both normal and neoplastic cells. Recent studies indicate an important role for TGF-.beta. in cells of the immune system (J. Kehrl et al., J. Exp. Med., 163:1037 [1986]; H-J. Ristow, Proc. Natl. Acad. Sci. U.S.A., 83: 5531 [1986]; and A. Rook et al., J. Immunol., 136:3916 [1986]) and connective tissue (M Sporn et al., Science, 219:1329 [1983]; R. Ignotz et al., J. Biol. Chem., 261:4337 [1986]; J. Varga et al., B.B.Res.Comm., 138:974 [1986]; A. Roberts et al., Proc. Natl Acad. Sci. U.S.A., 78:5339 [1981]; A. Roberts et al., Fed Proc., 42:2621 [1983]; and A. Roberts et al., Proc. Natl. Acad. Sci. U.S.A., 83:4167 [1986]), as well as epithelia (T. Matsui et al., Proc. Natl. Acad. Sci. U.S.A., 83:2438 [1986]and G. Shipley et al. Cancer Res., 46:2068 [1986]). Moreover, TGF-.beta. has been described as a suppressor of cytokine (e.g., TNF-.alpha.) production (Espevik et al., J. Exp. Med., 166: 571-576 [1987]) and as a promoter of cachexia (Beutler and Ceramic, New Eng. J. Med., 316: 379ff [1987]).
TGF-.beta. is multifunctional, since it can either stimulate or inhibit cell proliferation, can either stimulate or inhibit differentiation, and can either stimulate or inhibit other critical processes in cell function (M. Sporn, Science 233:532 [1986]).
The multifunctional activity of TGF-.beta. is modulated by the influence of other growth factors present together with the TGF-.beta.. TGF-.beta. can function as either an inhibitor or an enhancer of anchorage-independent growth, depending on the particular set of growth factors, e.g., EGF or TGF-.alpha., operant in the cell together with TGF-.beta. (Roberts et al., Proc. Natl. Acad. Sci. U.S.A., 82:119 [1985]). According to Brinkerhoff et al., Arthritis and Rheumatism, 26:1370 (1983), TGF-.beta. can act in concert with EGF to cause proliferation and piling up of normal (but not rheumatoid) synovial cells. Furthermore, Chua et al., J. Biol. Chem., 260:5213-5216 [1983]reported that TGF-.beta. induced collagenase secretion in human fibroblast cultures, and A. Tashjian et al., Proc. Natl. Acad. Sci. U.S.A., 82:4535 [1985] observed that TGF-.beta. stimulated the release of prostaglandins and mobilization of calcium. TGF-.beta. also has been reported to inhibit endothelial regeneration (R. Heimark et al., Science, 233:1078 [1986]).
U.S.S.N. 500,833, supra, relates to the use of TGF-.beta. to repair tissue in animals, in particular for use in accelerating wound healing by stimulating cell proliferation. In addition, Sporn et al., Science, 219: 1329-1331 (1983) and U.S. Pat. Nos. 4,810,691 and 4,774,228 describe the use of TGF-.beta. for promoting connective tissue deposition.
U.S. Ser. No. 07/116,101 filed Nov. 3, 1987, corresponding to EP Pub. 269,408, published June 1, 1988, and EP Pub. 213,776, corresponding to U.S. Pat. No. 4,806,523, disclose use of TGF-.beta. as an immunosuppressant, to treat inflammatory diseases such as rheumatoid arthritis.
It has been found that septic shock and invasive infection are diseases caused by humoral mediators of both exogenous and endogenous origin. Thus, release of tumor necrosis factor (TNF), followed by interleukin-1 (IL-1) and interferon-gamma (IFN-.gamma.), participates in the cascade of events noted in Gram-negative sepsis. Hesse et al., Surg. Gynecol. Obstet., 166: 147-153 (1988); Michie et al., N.Eng.J.Med., 318: 1481-1486 (1988); Espevik et al., J. Immunol., 140: 2312-2316 (1988).
Antibodies to TNF were found to protect mice from the lethal effect of endotoxin (Beutler et al., Science, 229: 869-871 (1985)). In addition, anti-cachectin/TNF monoclonal antibodies administered two hours before bacterial infusion conferred protection against septic shock and death in baboons. Tracey et al., Nature, 330:662-664 (1987). However, it has also been suggested that TNF and IL-1 participate in the mediation of endotoxin.induced enhancement of nonspecific resistance to intraabdominal infection and radiation sickness Urbaschek et al., Rev. Infect Dis., 9: S607-S615 (1987).
Monoclonal antibodies directed against endotoxin or its components have been evaluated for their utility in immunotherapy of Gram-negative sepsis. Thus, for example anti-core lipopolysaccharide (E. coli) has been reported to reduce mortality significantly in severely septic patients (E. Zeigler et al., N. Enz. J. Med., 307: 1225 (1982)). Also, murine and human monoclonal antibodies directed against the core lipopolysaccharide of the endotoxin were found to exert protection during Gram-negative bacterial sepsis in animals. Dunn, Transplantation, 45: 424-429 (1988); EP Publ. No. 183,876 published June 11, 1986; EP Publ. No. 174,204 published Mar. 12, 1986. Antibodies directed against lipid A also had a protective effect in humans. Jaspers et al., Infection 15 Suppl. 2: S89-95 (1987). Antibodies to the J5 mutant of E. coli are reported to be protective against septic shock in animals and humans. Cohen et al., Lancet, 1:8-11 (1987); Law and Marks, J. Infect. Dis., 151: 988-994 (1985). Antibodies to endotoxin core glycolipid were found to prevent the serious consequences of Gram-negative infections in surgical patients. Baumgartner et al., Lancet, 2: 59-63 (1985). In addition human monoclonal antibodies to P. aeruzinosa exotoxin A and exoenzyme S have been described as useful for this purpose. U.S. Pat. No. 4,677,070 issued June 30, 1987 and EP 243,174 published Oct. 28, 1987, respectively.
The clinical utility of these approaches using antibodies is being evaluated, but it is believed that they may suffer from some disadvantages such as unfavorable kinetics, biological half-life, and the potential for anti-idiotypic antibody generation that would neutralize the therapeutic antibody (in the case of human antibodies). In addition this immunotherapy only interdicts an early-stage effector.
It is an object of this invention to provide methods and compositions for the effective therapy and prevention of septic shock that do not rely on monoclonal antibody therapy.
This and other objects will become apparent to one of ordinary skill in the art.